Do not super-excess me!

The fact that carriers of β-thalassemia with a mutation in 1 of the 2 β-globin alleles would have almost normal hemoglobin levels and could perform well in many sports was even more puzzling. Pete Sampras, the legendary tennis player, has thalassemia minor,¹  which means that the synthesis of his β-globin protein is reduced. However, the inbalance between the amount of β- and α-chains did not preclude him from being one the most successful tennis players ever. The seminal article by Khandros and colleagues in this issue of Blood provides an explanation for this apparent paradox.²  They show that erythroid cells are equipped with a series of protein quality control responses that can eliminate, to a certain extent, the excess of α-chains produced in β-thalassemia.^2,–4  The authors show that detoxification of free α-globin involves activation of the ubiquitin proteasome system, autophagy, and heat-shock response. These observations place β-thalassemia in the category of protein aggregation diseases such as Parkinson, Alzheimer, Huntington, amyotrophic lateral sclerosis, and α1-antitrypsin deficiency.

Having characterized the protein quality control mechanism used by the erythroid cells to eliminate the excess of α-chains, we can now address fascinating questions, both old and new. In β-thalassemia the role of apoptosis has been well established as the main cause of reduced production of red cells. Formation of hemichromes (α-chain/heme aggregates) has been clearly associated with erythroid cell death.⁵  However, the extent of this phenomenon and whether the erythroid cells might be armed with additional tools to limit the damage associated with the excess of α-chains in the attempt to maximize red cell production are still debated.⁶  The data from Khandros et al suggest that these mechanisms play an important role in mitigating the phenotype of this disorder. Their results also suggest that these mechanisms are likely responsible for preventing any serious problem in β-thalassemia carriers. Furthermore, we can also speculate that the relative ability of these mechanisms to eliminate the excess of α-chains from the erythroid cells might also play an important role in the phenotypic variability observed in this disorder. Alpha-thalassemia is another disorder in which these mechanisms likely play a major role. Additional studies will clarify these points.

The new observations from Khandros and colleagues also suggest a strong correlation between the excess of globin chains, their detoxification from the erythroid cells, and the degree of ineffective erythropoiesis. Therefore, it will be very interesting to investigate whether these responses modulate the phenotypic outcome in thalassemia disorders. If these mechanisms are shown to play a major role in limiting the effect of hemichromes on the ineffective erythropoiesis, new potential pharmacologic approaches might aim at increasing the elimination of these supernumerary molecules.

Recent data support the notion that modulation of the formation of hemichromes can profoundly alter ineffective erythropoiesis in β-thalassemia. Both administration of transferrin and increased expression of hepcidin can decrease erythroid iron intake,^7,8  with subsequent reduction of hemichrome formation and amelioration of red cell morphology, production, and lifespan. In both cases, this was associated with increased hemoglobin levels. These observations support the data and the model proposed by Khandros and colleagues, in which elimination of some of the α-chains in excess allows production of better-quality red cells, while inhibition of the detoxification process increases the ineffective erythropoiesis. Interestingly, in animals in which transferrin or hepcidin were used as potential therapeutic tools, reduction of hemichrome formation was associated with diminished heme synthesis. This suggests that, potentially, the α-chains in excess might be disposed even more efficiently if they have fewer chances to aggregate with heme. Even this notion could be used to further enhance the ability of the detoxifying pathways to ameliorate the erythropoiesis in this disorder.

Moreover, the observation by Khandros et al might also prove useful in gene therapy for sickle cell anemia. It has been proposed that insertion of a normal β-globin gene into the hematopoietic stem cells of sickle cell patients might reduce the formation of the abnormal tetramers and reduce or prevent the formation of sickle red cells and the pathophysiologic sequelae associated with this phenomenon.⁹  However, the main concern associated with this approach is that, after gene transfer, the total amount of β-chains (sickle + normal) might exceed the amount of α-chains, leading to an α-thalassemia–like phenotype. The data from Khandros and colleagues suggest that a moderate excess of globin chains might be tolerated and eliminated efficiently by the erythroid cells.¹⁰  In conclusion, these novel findings will modify understanding of β-thalassemia and suggests new approaches to alleviate the symptoms of this disorder.